Abstract Our group previously developed a facile access to versatile ?-oxo gold carbenes via gold-catalyzed intermolecular oxidation of readily available alkynes. Two salient features of this strategy are a) the avoidance of hazardous and potentially explosive ?-diazo carbonyl compounds and b) the exceptionally electrophilic nature of the carbene center. Despite various synthetic methods developed by us and other researchers based on this approach, the arguably most valuable transformation of metal carbenes, i.e., concerted insertion into unactivated C(sp3)-H bonds and their enantioselective versions, have not been realized by our oxidative gold catalysis until a recent preliminary study by us. Moreover, deactivated C(sp3)-H bonds have mostly not been succumbed to carbene insertions. In this proposal, we aim to address these critical shortcomings and demonstrate that the advantages of this approach over the mainstream Rh-diazo chemistry are much beyond the improvement of safety. Electron-withdrawing group-substituted ?-oxo gold carbenes will be generated via gold-catalyzed intermolecular oxidation of electron-deficient alkynes. These acceptor/acceptor-type carbenes are of exceptional electrophilicity and, coupled with sufficient steric shielding, are capable of intramolecular insertions into C(sp3)-H bonds, thereby affording highly efficient and streamlining access to a large array of these cyclic ketones including various bicyclic and polycyclic ones. By adjusting the EWG, the gold catalyst, and the reaction conditions, the reactivities of the gold carbene moiety can be substantially tuned to accommodate not only unactivated C-H bonds but also deactivated ones. In contrast, the mainstream Rh-diazo approach is mostly incapable of insertion into deactivated C-H bonds due to the generally lesser reactivity of the Rh carbene counterparts. By the use of newly designed chiral NHC ligands, enantioselective C-H insertions by these highly reactive gold carbenes would enable the synthesis of chiral cyclopentanones with high e.e., in contrast to the moderate e.e. (?80%) in the Rh-diazo approach, and asymmetric functionalization of deactivated C-H bonds. This strategy would also offer significant benefit in synthetic planning, as it enables a completely novel entry into C-H insertion and presents unique solutions in terms of functional group compatibility and protecting group strategies, as C-C triple bonds are distinctively different from carbonyl in tolerance of various reaction conditions. Moreover, the rich chemistry of alkyne synthesis enables ready access to alkyne substrates with well-controlled stereochemistries, the diazo carbonyl counterparts of which may require extraordinary efforts. As such, our approach would open uncharted yet efficient access to valuable functional products, which would otherwise be practically inaccessible or synthetically prohibitively inefficient via the diazo chemistry. The synthetic utility of this oxidative C-H insertion will be demonstrated in a succinct total synthesis of picrotoxinin, where insertion into a deactivated C-H bond would serve as a streamlining step.